This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Brains disease caused by the human AIDS virus (termed HIV) has been linked to HIV's ability to grow well in microglia (MG). These cells reside in the central nervous system (CNS) and originate from bone marrow. A brain disease-causing strain of the monkey AIDS virus (termed simian immunodeficiency virus (SIV)) was generated by isolating infected MG and re-inoculating them into new monkeys. After three such passages, the progeny SIV reliably induced CNS disease in monkeys. Based upon these results, we postulate that the ability of an AIDS virus to replicate efficiently in MG represents a hallmark of AIDS virus-associated brain disease. We further postulate that the envelope gene of HIV that has been adapted to cultured human MG will confer the ability to cause brain disease to a simian-human immunodeficiency virus (SHIV) that contains this gene. SHIVs are hybrid viruses that are part SIV and part HIV, including the HIV envelope gene. We have constructed a novel SHIV, SHIV-Bo159N4, which contains the envelope gene of a primary HIV strain that was adapted in cultured human MG. Our new virus, SHIV-Bo159N4, replicated well in blood cells of all monkeys tested. Like the original HIV strain, our SHIV-Bo159N4 enters cells through a molecule called CCR5. Cells infected with our new virus form giant cells that contain many nuclei. Our overall goal is use our novel SHIV in monkeys to: Aim 1: Test the hypothesis that strong MG tropism of HIV Envelope will translate into neurovirulence in monkeys infected with a SHIV encoding the corresponding envelope gene. Aim 2: Increase SHIV neurovirulence by serial passage through infected MG in macaques. SHIV-infected animals will be followed prospectively for viral, hematological and neurological parameters. These studies are designed to generate an R5 SHIV model for AIDS virus-induced brain disease.